Discovery of Compounds to Inhibit Cancer EMT Genes in Order to Target Metastasis

描述（由申请人提供）：本基金提出的工作的总体目标是寻找有助于预防转移的新药。在第一阶段，将测试新获得的天然产物提取物，以寻找特异性靶向几种不同肿瘤细胞模型中上皮细胞向间充质细胞转化（EMT）关键基因的化合物。许多证据表明肿瘤细胞是通过EMT过程转移的。一组基因的转录在EMT中发生改变，这种改变与转移潜力相关。一种可以阻断这些基因表达变化的药物可能直接针对转移。此外，有证据表明EMT可能会使肿瘤细胞产生耐药性。定量高通量基因芯片分析ArrayPlate将测试提取物对EMT基因表达特征的影响。这些提取物是从索诺兰沙漠植物和相关微生物中提取的，最近由亚利桑那大学的西南天然产物研究和商业化中心分离出来。第二阶段将跟进第一阶段中确认的再次确认的命中馏分，馏分将进一步分离和重新测试，以试图分离和鉴定活性化合物。具有足够活性的化合物将在体外EMT模型和体内转移性癌症模型中进行测试。针对癌症EMT和阻断转移的新疗法可能对治疗特定类型的癌症有用，特别是与其他药物方案联合使用，并可能有助于减少耐药性。公共卫生相关性：转移，即细胞离开肿瘤部位并扩散到其他部位的能力，是癌症死亡的主要原因。最近的证据表明，存在一种通用的基因重编程机制，用于所有肿瘤的转移。这项资助的目标是发现一类新的抗癌药物，这种药物不会阻止肿瘤细胞的生长，而是通过干扰这种基因重编程机制直接阻止转移。

DESCRIPTION (provided by applicant): The overall objective of the work proposed in this grant is to find novel drugs that help to prevent metastasis. In Phase I, newly available natural product extracts will be tested to find compounds that specifically target genes that are critical for the Epithelial to Mesenchymal Transition (EMT) in several different tumor cell models. Many lines of evidence suggest that tumor cells become metastatic through the EMT process. Transcription of a set of genes is altered in EMT, and the alterations correlate with metastatic potential. A drug that can block these gene expression changes may directly target metastasis. In addition, evidence suggests that EMT may allow tumor cells to become drug resistant. A quantitative high-throughput gene chip assay, ArrayPlate, will test extracts for their effect on the EMT gene expression signature. The extracts are derived from Sonoran desert plants and associated microorganisms recently isolated by the Southwest Center for Natural Product Research and Commercialization, at the University of Arizona. Phase II will follow up on reconfirmed hit fractions identified in Phase I. Fractions will be further separated and retested to attempt to isolate and identify active compounds. Compounds with sufficient activity will be tested in in vitro EMT models and in in vivo models of metastatic cancer. Novel therapeutics that target cancer EMT and so blocking metastasis may be useful in treating particular types of cancer especially in combination with other drug regimens, and may help reduce drug resistance. PUBLIC HEALTH RELEVANCE: Metastasis, the ability of cells to leave a tumor site and spread to other sites, is the major cause of death in cancer. Recent evidence suggests that there is one general mechanism of genetic reprogramming that is used by all tumors in becoming metastatic. The goal of this grant is to discover a new class of cancer drugs that will not stop the growth of tumor cells, but instead directly block metastasis, by interfering with this genetic reprogramming mechanism.